chr2-47414415-T-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 4P and 3B. PM1PM2BP4BP6_Moderate

The NM_000251.3(MSH2):c.939T>A(p.Phe313Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,401,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F313S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 26)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.256

Publications

0 publications found

Variant links:

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

MSH2 Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
Lynch syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
Muir-Torre syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
mismatch repair cancer syndrome 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
ovarian cancer
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
malignant pancreatic neoplasm
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
prostate cancer
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
rhabdomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
breast cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MSH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 23 benign, 37 uncertain in NM_000251.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.36452544).

BP6

Variant 2-47414415-T-A is Benign according to our data. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47414415-T-A is described in CliVar as Likely_benign. Clinvar id is 4111015.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.939T>A	p.Phe313Leu	missense_variant	Exon 5 of 16	ENST00000233146.7	NP_000242.1	P43246-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 link	c.939T>A	p.Phe313Leu	missense_variant	Exon 5 of 16	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.14e-7

AC:

AN:

1401440

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

696856

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30158

American (AMR)

AF:

0.00

AC:

AN:

34648

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24386

East Asian (EAS)

AF:

0.00

AC:

AN:

38744

South Asian (SAS)

AF:

0.00

AC:

AN:

77542

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48430

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5210

European-Non Finnish (NFE)

AF:

9.22e-7

AC:

AN:

1084988

Other (OTH)

AF:

0.00

AC:

AN:

57334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.50

T;.;.;.

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.53

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.94

D;D;T;T

M_CAP

Benign

0.067

MetaRNN

Benign

0.36

T;T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.8

L;.;.;.

PhyloP100

0.26

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.8

N;N;.;N

REVEL

Uncertain

0.60

Sift

Benign

0.49

T;T;.;T

Sift4G

Benign

0.78

T;T;.;T

Polyphen

0.013

B;.;.;B

Vest4

0.93

MutPred

0.51

Loss of catalytic residue at F313 (P = 0.0088);.;Loss of catalytic residue at F313 (P = 0.0088);Loss of catalytic residue at F313 (P = 0.0088);

MVP

0.98

MPC

0.0073

ClinPred

0.22

GERP RS

0.19

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.23

gMVP

0.57

Mutation Taster

=39/61

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over